After 8 hours of contentious discussion, an advisory committee to the U.S. Food and Drug Administration (FDA) today endorsed the effectiveness of a first-of-its-kind peanut allergy treatment. By a seven-to-two vote, the panel concluded that the treatment, known as AR101, can reduce allergic reactions from accidental exposure to peanuts. The committee also voted eight to one to endorse a safety plan FDA has proposed; it would be used, along with available safety data, to support the treatment’s use in children and teenagers.

FDA is not bound to follow its advisory committees’ advice but often does. It will now weigh whether to approve the treatment, which is marketed by the company Aimmune Therapeutics headquartered in Brisbane, California.

The vote marks a turning point for the food allergy field, where the treatment—ingesting gradually increasing doses of peanut protein, in hopes of helping the immune system learn to tolerate it—has captured the attention of patients, families, and doctors. Called oral immunotherapy, it’s already offered by about 200 allergists in the United States who give patients calibrated doses of peanut products in the doctor’s office and at home. But hundreds more doctors have been waiting for FDA’s approval of Aimmune’s version, a designated capsule that contains powder derived from peanut flour and holds peanut proteins at consistent levels.

Aimmune formed in 2011; it received $ 3.5 million in early support from Food Allergy Research & Education (FARE), an advocacy group headquartered in McLean, Virginia, whose members desperately wanted something more than what physicians had to offer at the time: strict avoidance of peanuts, and epinephrine shots in case of accidental exposure and allergic reactions. (FARE subsequently sold its stake in Aimmune for $ 47 million.) Aimmune followed a decades-old approach to tackling allergies, but one that hadn’t yet been approved for any food allergies. Called immunotherapy, it involves exposing patients to gradually increasing doses of what they’re allergic to, in hopes that their immune system can learn to tolerate it. Injections for people with allergies to bee venom, pollen, and pet dander have been around for years.

Aimmune configured an oral immunotherapy for children allergic to peanuts, who number about 6 million in the United States. In the company’s phase III clinical trial, participants gradually ramped up their dose, beginning at under one-500thof a peanut and flattening out at a maintenance dose equivalent to about one peanut. Although Aimmune is seeking approval to sell the treatment for use in 4- to 17-year-olds, one of its executives recommended at today’s meeting that people taking its product continue indefinitely after their 18thbirthday, to help them stay protected. Previous studies have shown that stopping oral immunotherapy can cause the immune system to revert a more highly allergic state, although this remains a topic of investigation.

A conundrum

The advisory committee, made up of academic and government scientists, faced a conundrum. Aimmune’s treatment, AR101, helped children tolerate higher doses of peanut than before: Among the 294 highly allergic young people who completed its yearlong phase III study, 84% could tolerate two peanuts with no more than mild symptoms, and 63% could tolerate three. Assuming they continued on treatment, the company and doctors involved in the trials believed this meant that those young people were very likely better protected from what many of their parents fear the most—accidental exposure at school, birthday parties, friends’ homes, and elsewhere.

But advisory committee members worried that with AR101, patients were trading one risk for another. Because treatment means consuming the food proteins they are allergic to, trial participants were much more likely to suffer an allergic reaction, like abdominal pain, vomiting, or an itchy mouth and throat, than children not in trials who practiced avoidance of peanuts. (Aimmune also recommends that even when successfully taking its therapy, avoidance of peanut products continue, and data on accidental exposures among those taking AR101 was limited.) A meta-analysis of a dozen trials of oral peanut immunotherapy found that the likelihood of needing epinephrine was roughly triple for patients on treatment versus those not. Among 709 people taking AR101 in two Aimmune trials, 74 needed at least one dose of epinephrine to prevent a reaction from escalating. Twenty percent of participants dropped out of the phase III study because of side effects.

Furthermore, taking AR101 requires care: Exercise, hot showers, having a cold or a fever, menstruating, or being sleep deprived after ingesting a dose can all make an allergic reaction to the product more likely. In Aimmune trials, “The practice was to advise patients and families to be able to observe [children] for at least 2 hours” after a dose, said Stacie Jones, chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital in Little Rock, and one of the study investigators. “So not to put that child to bed, send to day care, [or] put on the bus” to school. The risk of an allergic reaction to treatment appeared highest in the early months of treatment, Aimmune executives noted, and the company is continuing to follow its volunteers.

Still, some on the committee worried that even on the maintenance dose—which continues indefinitely—patients could react one day when they hadn’t the day before. “Reactions occur unpredictably to previously tolerated doses,” said John Kelso, a staff physician in allergy and immunology in the Scripps Clinic in San Diego, California. He was one of the two who voted against AR101’s effectiveness; the other was Andrea Apter, who works in allergy and immunology at the Hospital of the University of Pennsylvania. “This is a lifetime treatment,” she said, “and we don’t have a lot of long-term data,” including in adults.

In one group of 310 people on a maintenance dose of AR101, nearly 9% experienced anaphylaxis, a type of allergic reaction that involves at least two body systems and is considered especially risky. Among those 310 people, 101 had an allergic reaction considered “moderate,” and eight had a reaction deemed severe. There have been no deaths connected to the treatment.

Risk versus benefit

Parents, adults and children with peanut allergies, and advocates who spoke during a public hearing this afternoon contended the risks and hassle were more than worth it. “Many patients are willing to accept some risk of new treatments,” said Lisa Gable, CEO of FARE. “That decision should lie with them.” Gable and others also stressed the difference between reactions that are more predictable and occur in the context of treatment, and can quickly be addressed, and those that come out of the blue.

Families also described the extreme anxiety they experience when raising an affected child. “Forty percent of parents believe their child has a very great chance of dying from a food allergy,” said Pamela Guerrerio, chief of the Food Allergy Research Unit at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, who provided an overview of current allergy treatment early in the meeting. In reality, deaths caused by food allergies are exceedingly rare, and annual estimates range from fewer than 10 to more than 150 in the United States. But the uncertainty around when peanuts will be encountered can be stressful.

FDA’s proposed a safety plan, if AR101 gets approved, calls for having caregivers or patients pledge that they will always carry injectable epinephrine while taking the drug. It also calls for administering a patient’s first dose, and every increased dose, in a “certified facility” that can treat allergic reactions. How facilities will become certified is still to be determined.

As FDA moves to internal discussions, another peanut allergy treatment is coming down the pipeline: a skin patch by DBV Technologies, which submitted a licensing application to FDA last month. It will be considered for approval in the coming months.

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